Pancreatic cancer (PCa) is one of the deadliest cancers with very poor prognosis. New effective methods for therapy of PCa are urgently needed. Radioimmunotherapy (RIT) relies on antigen-antibody binding to deliver cytotoxic doses of alpha- or beta radiation to tumor cells. RIT has been successfully used to treat refractory and recurrent lymphomas, with two radiolabeled monoclonal antibodies (mAb) targeted against CD20 (Zevalin(R) and Bexxar(R)). Very recently FDA has approved Zevalin as a first-line therapy for newly diagnosed patients with non-Hodgkin lymphoma (NHL). The power of RIT in comparison with many other therapeutic modalities is its cytocidal nature when particulate radiation emanating from the mAbs causes physical destruction of the cell. In addition, RIT has excellent safety record having much less side effects than conventional chemotherapy and is not a subject to multidrug resistance mechanisms. However, in PCa RIT has shown very modest results both pre-clinically and in patients with unresectable PCa. The reasons for RIT not being able to deliver sustained responses in PCa may be due to the wrong choices of targeted antigens and radionuclides. Obviously, new choices of targeted antigens and more powerful radionuclides are needed to make RIT successful in treatment of PCa. Targeting of intracellular antigens (IntAs) was pioneered by Dr. A. Epstein as an alternative to targeting surface antigens in RIT. IntAs become accessible for mAb binding in aggressively growing tumors as a result of fast cellular turnover. The advantage of this approach is that mAbs to IntAs have very low cross-reactivity with surface antigens on healthy tissue which leads to high specificity and low toxicity of treatment. This approach is currently is tested in the clinic - Dr. Epstein is conducting a clinical trial of radiolabeled mAb to intranuclear histones in patients with advanced lung cancer;while Dr. Dadachova's group is targeting melanin pigment with radiolabeled melanin-binding mAb in patients with metastatic melanoma. We hypothesize that by targeting intranuclear histones in PCa with specific mAb radiolabeled with powerful in vivo generator of alpha-particles 212-Lead/212-Bismuth (212Pb/212Bi) - we will be able to deliver high tumoricidal doses to the tumors without toxicity to normal tissues. We also hypothesize that by pre-treating tumors with chemotherapeutic agents such as cisplatin or gemcitabine - we will make some tumor cells non-viable thus making more of the intranuclear histones accessible for radiolabeled specific mAb which should result in increased tumor uptake and better therapy results. The project proposes to investigate the systemic treatment of PCa with radiolabeled mAbs to intranuclear histones. If successful, this approach offers the possibility of cure for PCa. PUBLIC HEALTH RELEVANCE: The project proposes to investigate the systemic treatment of PCa with radiolabeled mAbs to intranuclear histones and employs a novel idea of targeting intranuclear antigens with specific mAbs in aggressive fast growing PCa in combination with powerful alpha-particle emitting in vivo radionuclide generator 212Pb/212Bi. If successful, this approach offers the possibility of cure for PCa.